IgE is thought to play a central role in promoting airway inflammation and asthma but the molecular mechanisms for its production and for its role in the regulation of airway inflammation have not been well elucidated. Our preliminary data show that mice deficient in lymphotoxin (LTalpha-/-), a proinflammatory cytokine, are also severely deficient in IgE, yet paradoxically exhibit a spontaneous Th1-dominant airway inflammation and a gradual remodeling of the airways. IgE+ cells are initially elevated in the gut associated lymphoid tissues and migration of B cells into the gut is severely impaired in LT-deficient mice. Therefore, the physiological role of lgE in normal airway physiology and the major site for IgE production should be revisited. We hypothesize that a LT-mediated microenvironment in the gut is essential for IgE production and the lack of IgE impairs a Th2-mediated response and/or promotes a Th1-type of airway inflammation. This raises the possibility that some asthmatics are associated with reduced IgE levels with Th1-dominant airway inflammation while others have elevated IgE and Th2 dominant inflammation yet suffers from similar symptoms. LT-deficient mice may provide a unique model to study how IgE influences Th1 differentiation and how a Th1-dominant environment in turn, affects a Th2 response. Our major objective is to determine the mechanisms by which LT regulates IgE production and Th1 airway inflammation as well as to redefine the role of lgE and mast cells in airway inflammation. In particular, we seek to identify: 1) where and how LT regulates IgE production, 2) how IgE levels influence mast cell development for airway inflammation and bronchial hyperresponsiveness (BHR); and 3) how LT influences T-helper cell differentiation as well as how existing Th1 cells can influence IgE production and a Th2 response. We will explore whether IgE is required for mast cell development and maturation that then initiate Th2 response via their early release of lL4. Understanding how LT, mast cells, and IgE levels regulate airway inflammation will lead to a better understanding of parallel mechanisms that may operate in subsets of asthmatic patients, and guide future immunotherapies for asthma.